This proposal is a continuation of previously funded studies examining the role of adenosine receptors in the regulation of aqueous humor dynamics and their potential as antiglaucoma drugs. Glaucoma is a blinding disorder where the elevation in intraocular pressure (IOP) is considered the primary risk factor. Little doubt now remains that adenosine plays a significant role as a neuromodulator and autacoid in cell-to-cell communication. Recent biochemical, pharmacological, physiological and molecular studies have converged to demonstrate that the responses to adenosine and adenosine agonists are mediated by multiple receptor subtypes and signal transduction pathways. Work presented in this proposal demonstrates that adenosine agonists are effective modulators of IOP. However, the receptor subtypes, sites and mechanisms responsible for the ocular effects of adenosine agonists are not completely understood. This proposal is based on the hypothesis that adenosine agonists regulate aqueous humor dynamics at multiple ocular sites and by a variety of cellular mechanisms.
The specific aims of this project are: 1) to determine the receptor subtypes responsible for adenosine agonists' effects on IOP in monkeys, 2) to characterize adenosine receptor-mediated changes intotal outflow facility, 3) to characterize the adenosine receptor- mediated effects on trabecular and uveoscleral outflow, 4) to determine the receptor subtypes and signal transduction events associated with postjunctional adenosine receptors in the iris/ciliary body, 5) to determine the receptor subtypes and signal transduction events in culture systems of ciliary muscle and trabecular and nonpigmented ciliary epithelial cells, 6) to determine if enhanced production and release of endogenous adenosine can modulate aqueous humor dynamics and 7) to determine if adenosine receptor activation is involved in epinephrine-induced ocular hypotension. The projected results of this project are: 1) an improved understanding of the sites and mechanisms that regulate aqueous humor dynamics, 2) elucidation of the cellular signal transduction mechanisms involved in the regulation of aqueous humor dynamics thaat may serve as new targets for signal transduction-directed therapies and 3) a rational basis for the use of adenosine agonists in glaucoma therapy.
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